Abstract 5165: The genomic landscape and prognostic implications of somatic alterations in patients (pts) with ER+, HER2-, PIK3CA mutated (mut) advanced breast cancer treated with taselisib and fulvestrant
Authors: Jessica W. Chen, Susan Dent, William Jacot, Javier Cortés, Ian E. Krop, Thomas J. Stout, Frauke Schimmoller, Heidi M. Savage, Katherine E. Hutchinson, Timothy R. Wilson
Journal: Cancer Research (2022)

Abstract Background: Mutations in PIK3CA, encoding the catalytic subunit p110α of PI3K, are present in ~40% of ER+/HER- BC. Taselisib (TAS) is a potent and selective β-sparing PI3K inhibitor that improves outcomes in combination with endocrine therapy in pts with PIK3CAmut advanced breast cancer (aBC). To better understand the molecular alterations associated with response to PI3K inhibition, we profiled the genomic landscape of ctDNA collected from PIK3CAmut, ER+, HER2- aBC pts immediately prior to treatment (tx) with TAS or placebo (PBO) plus fulvestrant (FUL). Methods: Pts were enrolled as part of a phase III randomized study of TAS or PBO plus FUL in ER+, HER2- PIK3CAmut aBC (SANDPIPER, NCT02340221). Pre-tx ctDNA samples from 508 pts underwent comprehensive genomic profiling using the FoundationOne Liquid NGS assay at Foundation Medicine, Inc.; the 339 pts with PIK3CAmut ctDNA were further analyzed herein. The top mutated genes were analyzed for prognostic value against investigator-assessed progression-free survival (PFS) for both tx regimens using Cox proportional hazards regression modeling. As analysis was exploratory, no adjustments were made for multiple testing. Results: The top altered genes were TP53 (44%), ESR1 (37%), CDH1 (17%), FGFR1 (12%), NF1 (11%), CHEK2 (10%), and PTEN (9%). In pts treated with PBO+FUL, alterations in PTEN (HR 2.8; 95% CI 1.4-5.7; p=0.0107) and TP53 (HR 2.0; 95% CI 1.3-3.1; p=0.0025) were associated with a worse prognosis compared to pts with no mutation detected (NMD) in these genes. In pts treated with TAS+FUL, alterations in FGFR1 (HR 2.4; 95% CI 1.5-3.7; p=0.0006), TP53 (HR 1.9; 95% CI 1.4-2.6; p=0.0001) and PTEN (HR 1.8; 95% CI 1.1-2.8; p=0.0265) were associated with a worse prognosis compared to pts with NMD in these genes. Alterations in ESR1, CDH1, or CHEK2 were not associated with prognosis (p≥0.05) in either tx arm. A trend towards worse prognosis was observed in pts with NF1 altered ctDNA treated with PBO+FUL (HR 2.1; 95% CI 1.1-4.1; p=0.0527), which was not observed in pts treated with TAS+FUL (HR 0.97; 95% CI 0.57-1.65; p=0.901). Within the NF1-altered subgroup, a significant PFS difference was observed between TAS- vs PBO-treated pts (HR 0.28; 95% CI 0.11-0.67; p=0.0058; median 5.65 vs 1.94 months, respectively). Conclusions: We report that the most frequently mutated genes identified are consistent with previous studies in pts with ER+, HER2- aBC. This analysis shows that alterations in TP53 and PTEN were associated with poor prognosis in both tx arms, and FGFR1 alterations were associated with a poor prognosis in TAS+FUL treated pts. Further, NF1 alterations were associated with a poor prognosis in PBO+FUL treated pts, an association that was not observed with TAS+FUL. These findings may inform future rational combination strategies for the clinical development of PI3K inhibitors. Citation Format: Jessica W. Chen, Susan Dent, William Jacot, Javier Cortés, Ian E. Krop, Thomas J. Stout, Frauke Schimmoller, Heidi M. Savage, Katherine E. Hutchinson, Timothy R. Wilson. The genomic landscape and prognostic implications of somatic alterations in patients (pts) with ER+, HER2-, PIK3CA mutated (mut) advanced breast cancer treated with taselisib and fulvestrant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5165.